1. Field of the Invention:
This invention relates to a material for oxygen-exchange membranes for gas-exchange devices such as artificial heart-lung machines that maintain the circulation of the blood and the oxygen supply during open heart surgery, oxygenators (artificial lung machines) that aid lung function for patients with lung insufficiency, extracorporeal membrane oxygenators (ECMO) used for extracorporeal circulation that is to be maintained for a long period of time, etc.
2. Description of the Prior Art
At present, there are the following three major categories of gas exchange devices (where venous blood is changed into arterial blood by the addition of oxygen and the removal of carbon dioxide from the blood) for commercially available artificial heart-lung machines that are used in open-heart surgery: (1) the kind with direct contact between gases and the blood (bubble type, film type, etc.), (2) the kind with small pores (the type in which gas exchange occurs via pores with the diameter of several hundreds to several thousands of angstroms (the hollow fiber type, the layered type, etc.); and (3) the gas diffusion type (the type in which gas exchange is accomplished by the dissolution and the diffusion of the gas into a homogeneous membrane).
Of these, in category 1, venous blood is bubbled directly with oxygen to change the blood into arterial blood. By this method, because the blood is brought into direct contact with oxygen, erythrocytes are lysed, and the amount of free hemoglobin increases. That is, with this method, hemolysis occurs readily. Also, because oxygen gas is directly bubbled through, the gas remains in the blood in the form of fine bubbles. It is difficult to remove the bubbles, and they greatly damage the blood. For that reason, it is difficult to use this form of substitution for heart and lung function over long periods of time.
In category 2, in which gas exchange is through small pores, because there is no direct contact between the blood and the gas as in category 1, the two problems of damage to the blood corpuscles and the mixture of gas bubbles with the blood are solved. However, because the water components of the blood and also components of the plasma ooze through the pores, the gas-exchange function decreases with time. Also, the material of this kind of membrane is generally polypropylene or the like, and the compatibility of such substances with the blood is inferior. That is, if such substances are used, blood coagulation factors and complements are activated, and in addition, platelets and leukocytes readily agglutinate or are readily lysed. To control these reactions, large amounts of anticoagulant agents such as heparin are needed. When large amounts of heparin are administered, hemorrhage readily occurs, and presents a risk to survival. In this way, if a gas-exchange device of the second category is used for a long period of time, multiple organ insufficiency will occur because of hemorrhage and damage to blood components, making such use impossible.
Because the gas exchange by means of devices in the third category occurs via a homogeneous membrane, the problems of damage to blood corpuscles and the mixture of gas bubbles with the blood caused in devices of the first category are avoided, and the disadvantages of oozing of water and plasma components that occur with devices of category 2 are also overcome. This kind of membrane is generally manufactured from silicone rubber (silicone-type polymers). The compatibility of silicone rubber with the blood is better than that of other materials. Thus, of these gas-exchange devices in categories 1 to 3, the devices of category 3 seem to be most satisfactory. However, this kind of membrane has the following drawbacks. (a) Because silicone rubber by itself is not strong, either the membrane must be made thick so that strength can be provided, or else the rubber must be reinforced with a reinforcing material such as fillers. For this reason, the diffusion of gas is slowed, and the capability of oxygen exchange is decreased. (b) The compatibility of silicone rubber with the blood is not completely satisfactory, and because this material causes blood coagulation, large amounts of heparin must be given at the time of the use of the device, and for that reason, hemorrhaging readily occurs, presenting a danger to survival. (c) Activation of complement causes changes in the blood coagulation system, giving rise to increased permeability of the vessel walls to leukocytes, lymphocytes, etc., increased numbers of leukocytes, and so on. Therefore, treatment with use of a silicone membrane causes the development of fever or symptoms of shock, thus presenting a danger to survival or delaying convalescence after surgery. The longest period of time for which gas-exchange devices of this type can be used is two or three days; survival rates when such devices are used for longer periods are close to zero.
Research has been done into the following kinds of polymers, among others, as materials that might be used in place of the silicone rubber membrane in devices of category 3. As examples of an improved material in terms of strength (problem "a" mentioned above), a silicone-polycarbonate copolymer is disclosed in U.S. Pat. Nos. 3,419,634 and 3,419,635. Also, a method for the manufacture of thin membranes in which that copolymer is used is disclosed in U.S. Pat. No. 3,767,737. Japanese Laid-Open Patent Publication 61-430 discloses a selectively gas-permeable membrane made of a polyurethaneurea obtained by the reaction of diaminopolysiloxane, isocyanate, and compounds having a plurality of amino groups. In addition, in Japanese Patent Application 60-241567 (No. PM-80 for research into basic techniques for polymers), a selectively gas-permeable membrane made of a polyurethaneurea that is obtained by the reaction of diaminopolysiloxane, isocyanate, and polyhydric compounds having tertiary amino groups is disclosed. These polymers are relatively strong, but their compatibility with the blood cannot yet be said to be completely satisfactory, so that the problems described in sections b and c above have not been solved. Also, because the polymers disclosed in Japanese Patent Publication 61-430 and Japanese Patent Application 60-241567 have within their molecules a siloxane bond and a urea bond that have opposite polarities, the choice of a solvent for use during the preparation of the membrane is difficult, and it is difficult to make a thin membrane.
As materials that can solve the problem of blood coagulation described above in section b, a kind of polymer to which heparin is attached by ionic bond has been disclosed in Collected Papers on Polymers, 36, 223 (1979). The polymer is obtained by the following steps: tertiary amino groups of a terpolymer that contains dimethylaminoethylmethacrylate, methoxypolyethyleneglycol methacrylate, and glycidyl methacrylate are changed to tertiary ammonium groups, the resulting polymer is blended with polyurethane, and the mixture is heated so that a cross-linking reaction proceeds. The product that is obtained from this material releases heparin slowly from its surface, which prevents blood coagulation. However, gas permeation of this material is not satisfactory, and it cannot be used in an artificial heart-lung machine. An anti-blood-clotting elastomer made of polyurethane or polyurethaneurea that contains polysiloxane has been disclosed in Japanese Patent Publication 58-188458. However, the anti-blood-clotting properties of this elastomer are not satisfactory. Also, its permeability to gases is not satisfactory, and because the activation of complement is not controlled, the elastomer cannot be used for the applications described above.
Many materials exist in the field of dialysis membranes for use in artificial kidneys for dialysis that might be used to solve the problem of complement activation in the blood discussed above in section c. For example, in Jinko Zoki 16 (2), 818-821 (1987), it is reported that when a cellulose membrane modified with diethylaminoethyl groups is used, activation of complement during dialysis is markedly decreased compared to with the original cellulose membrane. However, because the permeability of this membrane to gases is poor, it is difficult to use the material as membranes for oxygenators (artificial lung machines).